Paclitaxel, an anticancer agent, shows excellent cytotoxicity to various kinds of cancers such as ovarian cancer, breast cancer, esophagus cancer, melanoma and leukemia. Paclitaxel formulation currently used in clinical remedies has been commercialized in the form of emulsion preconcentrate (self-emulsifying system) because its water solubility is very low even compared with an anti-cancer medicine of Bristol-Myers Squibb Company. Taxol® is a commercially available injection agent, in the form of solution, in which paclitaxel is mixed with solubilizing agent, that is, Cremophor EL (polyoxyethylene 35 castor oil, polyoxylethylaed castor oil and polyoxyethoxylated castor oil) in dehydrated alcohol (U.S. Pat. No. 5,438,072). It is known, however, that this agent has a limitation in directions and dosage because solubilizing agent in Taxol® causes toxic side effects. Therefore, many studies have been performed to develop new paclitaxel formulations with high stability and low toxic effects. There are many patents describing lipid emulsion, polymeric micelles and liposome. In emulsion formulation, not only emulsion using conventional oils and emulsifiers but also solid lipid nanoparticles, emulsion concentrate and so on have been patented. Also other solubilization techniques by utilizing liposome, polymeric nanoparticles and polymeric micelles have been developed. These formulations solubilizing paclitaxel took advantage of the accumulated technological advancement already developed for other insoluble drugs.
Also, even though paclitaxel is currently used to treat metastatic ovarian cancer and breast cancer, it is expected to be prescribed for various cancers, especially the metastatic solid tumors (e.g., lung cancer and hepatoma) in the near future. Therefore, market forecast is promising for paclitaxel.
From the pharmaceutical point of view, Taxol®, the most frequently prescribed paclitaxel formulation has a problem of forming precipitation when diluted inside the infusion bag due to the low solubility. In-line filter is used to prevent the precipitation from entering the blood stream of the patient. The exact dose of paclitaxel, therefore, is unknown and varies from time to time. Also, the plasticizer is known to leak out from the infusion bag made of PVC causing potential health problem. From the pharmacological point of view, Cremophor EL, the excipient can cause severe side-effects such as hypersensitivity, vasodilation, dyspnea, enervation and high blood pressure. From the pharmaceutical and pharmacological points of view, the stability and the safety of the drug must be improved by developing other administration routes and formulations.
The most promising and convenient administration route is considered to be the oral route. There is a big hurdle to overcome, however, since paclitaxel is not absorbed into the body due to the efflux mechanism by p-glycoprotein which exists in the epithelial cell of gastrointestinal tract. Many p-glycoprotein inhibitors are known up to date including cinchonin, calcium channel blockers such as verapamil and dihydropyridines (for instance nifedipine, nicardipine and nitrendipine), calmodulin antagonist such as trifluoroperazine, antihypertensive such as reserpine, Vinca alkaloids such as vincristine and vinblastine, steroids such as progesterone, antiarrythmics such as amiodarone and quinidine, anthelmintic such as quinacrine and quinine, and immunosuppressants such as cyclosporine A, staurosporine and tacrolimus.
In addition to the increased oral bioavailability of paclitaxel, the p-glycoprotein inhibitors can help overcome multi-drug resistance by inhibiting p-glycoprotein existing in the cancer cells. On the other hand, paclitaxel is known to be metabolized by hepatic microsomal enzyme. Paclitaxel converts to 6-α-hydroxypaclitaxel and 3′-p-hydroxypaclitaxel by CYP2C8 and CYP3A4, respectively.
Cyclosporin A inhibits the formation of 6-α-hydroxypaclitaxel. Doxorubicin, etoposide (VP-16) and cisplatin inhibit the formation of 3′-p-hydroxypaclitaxel. And verapamil and tamoxifen inhibit the metabolism of paclitaxel to 6-α-hydroxypaclitaxel and 3′-p-hydroxypaclitaxel. Therefore, co-administration of paclitaxel with the above mentioned metabolism inhibitors could also increase the bioavailability of paclitaxel.
Many formulations have been developed to solubilize paclitaxel. One of the most widely used and successful formulations is Taxol®. Lipid emulsion (U.S. Pat. No. 6,391,832 Medical emulsion for lubrication and delivery of drugs; U.S. Pat. No. 6,348,491 Oil-in-water emulsion for encapsulating paclitaxel) or pre-concentrate which forms transparent colloidal system in water (U.S. Pat. No. 6,267,985 Clear oil-containing pharmaceutical compositions; U.S. Pat. No. 6,294,192 Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents) are also well known. In case of pre-concentrate, clear oil composition forms dispersion of very small particles whose absorbance at 400 nm is less than 0.3.
The above formulation is distinctly different from the composition for solubilization of paclitaxel in the present invention. The composition in the present invention is coarsely dispersed in water, and the absorbance at 400 nm is above 0.38 in all cases and between 1 and 4 in most cases. In other words, efforts have been made to prepare nano-sized particles or its pre-concentrate to solubilize paclitaxel in the existing inventions whereas the current invention discloses the composition that does not disperse well and does disperse to form particles of a few micrometers in size if it does. The merits of the composition of the present invention include that paclitaxel does not precipitate out in the dispersion while it is a high mucoadhesive in the intestine.
One of the main obstacles in commercializing oral paclitaxel formulations is the problem of forming paclitaxel precipitation upon dilution with body fluid. Even if the formulation is stable before dilution, precipitation forms with time in the dispersion. Paclitaxel precipitation cannot be absorbed into the body in the intestine at all. Once the problem of precipitation formation is solved, however, another obstacle, efflux system of p-glycoprotein in the gastrointestinal tract, awaits lowering bioavailability of paclitaxel.
In the present invention, a mucoadhesive lipid, monoolein was used as a main component for oral delivery of paclitaxel. Even though paclitaxel is solubilized in monoolein, it forms precipitation in the cubic phase of the monoolein/water system. Therefore, we prepared an oily composition that does not form paclitaxel precipitation with time even after the composition is mixed with water. The cubic phase of the monoolein/water system is composed of ca. 60% (v/v) of water. On the other hand, when more than 10% of oil is added to monoolein, the mixture does not form cubic phase, but forms an amorphous composition that contains ca. 5˜10% of water. It is worthwhile to note that this composition does not form paclitaxel precipitation. Also, this composition is very mucoadhesive to intestinal wall.
To date, oral paclitaxel formulation that does not require p-glycoprotein inhibitor has not been developed. Also the bioavailability of the oral paclitaxel formulations was very low even when it is co-administered with p-glycoprotein inhibitor orally.
To overcome the problem of forming paclitaxel precipitation in contact with water and of low oral bioavailability as mentioned above, the present invention provides mucoadhesive compositions for solubilization of paclitaxel that have high bioavailability when administered alone or with p-glycoprotein inhibitor and the preparation method thereof.